page 625) now show that these inhibitors act locally and selectively despite circulating systemically. A better understanding of how this works could suggest ways to tackle the ectopic mineralization seen during arthritis.
Mineralization is necessary in bone, but must be prevented in soft tissues—such as artery walls and cartilage—that have an extensive, mineralization-prone extracellular matrix (ECM). It is unclear how this distinction is made by inhibitors that are made locally but also circulate systemically.
Murshed et al. investigated this process by expressing a known mineralization inhibitor, Matrix gla protein (MGP), in various mouse tissues. MGP could act locally when expressed locally: expression in arterial walls inhibited the ectopic mineralization normally seen there in mice lacking MGP; and expression in bone-generating osteoblasts reduced bone mineralization in wild-type mice. But MGP expressed in liver, so that it reached high levels in the bloodstream, did not have such effects. Although the resulting serum could inhibit osteoblast mineralization in vitro, there was no effect on either ectopic arterial wall mineralization or normal bone mineralization.
The authors confirmed that the mineral-binding gla (γ-carboxylated glutamic acid) residues of MGP are necessary for its inhibitor activity; the bone protein osteocalcin has similar gla residues but was found not to be a mineralization inhibitor. But the mechanism that keeps MGP action local remains to be determined. ▪